The distribution of body mass into muscle and fat tissues has profound implications for the health of an individual. Many factors are known to be involved in the balance of adipocyte and muscle cell differentiation. For example, glucocorticoids such as cortisol, the natural hormone, or a multitude of synthetic cortisol analogues (including prednisone, hydrocortisone and dexamethasone) act via the glucocorticoid receptor (GR) to regulate a large array of tissues and cell specific actions in most cells in the body. Glucocorticoids play a critical role in regulating differentiation decisions both in vivo and ex vivo, favoring adipogenesis and inhibiting muscle formation. Androgen administration has also been shown to influence body composition, reducing fat mass but increasing muscle mass.
In the development of obesity, the increase in adipose tissue mass can be due to an increase in both the size and number of adipocytes. The increase in cell number can result of recruitment of preadipocytes from a population of multipotent stem cells or from sub-populations of cells resident in mature white adipose tissue (WAT). Bone marrow mesenchymal stem cells (MSCs) can differentiate into a variety of cell types including fat, muscle, cartilage, and bone. With aging, marrow adipogenesis accelerates in vivo, while the ability of MSCs to form bone decreases. It has been suggested that MSC precursors differentiate into adipose rather than bone with a reciprocal relationship, and thus may contribute to age-related body composition changes.
Fat redistribution in the elderly is associated with an increased risk for metabolic syndrome, including diabetes, hypertension, dyslipidemia, atherosclerosis and relatively increased intra-abdominal fat.
There is also a decline in muscle bulk and performance associated with normal aging, often resulting from gradual onset of sarcopenia. Although skeletal muscle has the capacity to regenerate itself, this process is not activated in the elderly. It has been suggested that age-related changes within skeletal muscle tissue and the host environment affect the proliferation and fusion of myoblasts in response to injury in old animals.
Deficient or poor functioning muscle are among the most devastating childhood health issues. Such muscle diseases are found in patients with a diverse set of congenital myopathies and muscular dystrophies, such as Duchenne Muscular Dystrophy (DMD), that together affect more than 1 in 3000 children. These disorders are usually associated with either inherited or spontaneous genetic mutations. Children with these disorders suffer from a wide spectrum of complications, frequently causing devastating morbidities with significantly premature mortality. The current lack of effective therapies and the frequency of fatalities underscore the urgent need for developing novel treatment strategies.
Muscle tissue in adult vertebrates regenerates from stem cells known as satellite cells or muscle stem cells (MuSCs). Satellite cells are distributed throughout muscle tissue and are mitotically quiescent in the absence of injury or disease, residing in an instructive, anatomically defined niche. In addition to satellite cells, cell types that might contribute to muscle regeneration include, but are not limited to, mesangioblasts, bone marrow derived cells, muscle interstitial cells, mesenchymal stem cells. See D. D. Cornelison et al. (2001) Dev Biol 239, 79; S. Fukada et al. (2004) Exp Cell Res 296, 245; D. Montarras et al. (2005) Science 309, 2064; S. Kuang et al. (2007) Cell 129, 999; M. Cerletti et al. (2008) Cell 134, 37; C. A. Collins et al. (2005) Cell 122, 289; A. Sacco et al. (2008) Nature 456, 502; R. I. Sherwood et al. (2004) Cell 119, 543; and Galvez et al. (2006) J Cell Biol. 174(2):231-43.
Tissue engineering seeks to repair or replace damaged or diseased tissues of the body by implanting combinations of cells, biomaterial scaffolds, biologically active molecules, and genes. An underlying premise of this approach is that exogenously introduced cells will improve the speed and extent of tissue repair. Adult MuSCs can be transplanted into injured or defective skeletal musculature to reconstitute muscle fibers and improve function, potentially providing for the therapeutic applications for MuSCs. However, a major obstacle to translating this technology is the lack of understanding about how differentiation decisions are determined and tools to control and promote these decisions for therapeutic benefits have not been developed. Advancing these areas could pioneer a variety of novel therapeutic approaches for individuals with impaired muscle mass or function, or to address an imbalance between muscle and adipose tissue.